Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease.

BACKGROUND: Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. METHODS: This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. RESULTS: The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. CONCLUSIONS: Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.

Phase I Trial of Weekly Cabazitaxel with Concurrent Intensity Modulated Radiation and Androgen Deprivation Therapy for the Treatment of High-Risk Prostate Cancer.

PURPOSE: Cabazitaxel has been demonstrated to improve the overall survival for men with metastatic castrate-resistant prostate cancer. The purpose of this study was to determine the maximum tolerated dose for concurrent cabazitaxel with androgen deprivation and intensity modulated radiation therapy in men with high-risk prostate cancer. METHODS AND MATERIALS: Twenty men were enrolled in this institutuional review board-approved phase I clinical trial using a 3 + 3 design. Patients were followed prospectively for safety, efficacy, and health-related quality of life (Expanded Prostate Index Composite). Efficacy was assessed biochemically using the Phoenix definition. RESULTS: With a median follow-up time of 56 months, the maximum tolerated dose of concurrent cabazitaxel was 6 mg/m2. The 5-year biochemical disease-free survival was 73%, despite 75% of patients having very high risk prostate cancer per the National Comprehensive Cancer Network guidelines. Four patients were unable to complete chemotherapy owing to dose-limiting toxicities (eg, rectal bleeding, diarrhea, and elevated transaminase). There was no significant minimally important difference in Expanded Prostate Index Composite patient-reported outcomes for either the urinary or bowel domains; however, there was a significant decrease in the sexual domain. CONCLUSIONS: This is the first clinical trial of prostate cancer to report on the combination of cabazitaxel and radiation therapy. The maximum tolerated dose of concurrent cabazitaxel with radiation and androgen deprivation therapy was determined to be 6 mg/m2. Despite the aggressive nature of the disease, robust biochemical control was observed.

Development and Validation of a Novel Integrated Clinical-Genomic Risk Group Classification for Localized Prostate Cancer.

Purpose It is clinically challenging to integrate genomic-classifier results that report a numeric risk of recurrence into treatment recommendations for localized prostate cancer, which are founded in the framework of risk groups. We aimed to develop a novel clinical-genomic risk grouping system that can readily be incorporated into treatment guidelines for localized prostate cancer. Materials and Methods Two multicenter cohorts (n = 991) were used for training and validation of the clinical-genomic risk groups, and two additional cohorts (n = 5,937) were used for reclassification analyses. Competing risks analysis was used to estimate the risk of distant metastasis. Time-dependent c-indices were constructed to compare clinicopathologic risk models with the clinical-genomic risk groups. Results With a median follow-up of 8 years for patients in the training cohort, 10-year distant metastasis rates for National Comprehensive Cancer Network (NCCN) low, favorable-intermediate, unfavorable-intermediate, and high-risk were 7.3%, 9.2%, 38.0%, and 39.5%, respectively. In contrast, the three-tier clinical-genomic risk groups had 10-year distant metastasis rates of 3.5%, 29.4%, and 54.6%, for low-, intermediate-, and high-risk, respectively, which were consistent in the validation cohort (0%, 25.9%, and 55.2%, respectively). C-indices for the clinical-genomic risk grouping system (0.84; 95% CI, 0.61 to 0.93) were improved over NCCN (0.73; 95% CI, 0.60 to 0.86) and Cancer of the Prostate Risk Assessment (0.74; 95% CI, 0.65 to 0.84), and 30% of patients using NCCN low/intermediate/high would be reclassified by the new three-tier system and 67% of patients would be reclassified from NCCN six-tier (very-low- to very-high-risk) by the new six-tier system. Conclusion A commercially available genomic classifier in combination with standard clinicopathologic variables can generate a simple-to-use clinical-genomic risk grouping that more accurately identifies patients at low, intermediate, and high risk for metastasis and can be easily incorporated into current guidelines to better risk-stratify patients.

African American men with low-grade prostate cancer have increased disease recurrence after prostatectomy compared with Caucasian men.

PURPOSE: To explore whether disparities in outcomes exist between African American (AA) and Caucasian (CS) men with low-grade prostate cancer and similar cancer of the prostate risk assessment-postsurgery (CAPRA-S) features following prostatectomy (RP). METHODS: The overall cohort consisted of 1,265 men (234 AA and 1,031 CS) who met the National comprehensive cancer network criteria for low- to intermediate-risk prostate cancer and underwent RP between 1990 and 2012. We first evaluated whether clinical factors were associated with adverse pathologic outcomes and freedom from biochemical failure (FFbF) using the entire cohort. Next, we studied a subset of 705 men (112 AA and 593 CS) who had pathologic Gleason score≤6 (low-grade disease). Using this cohort, we determined whether race affected FFbF in men with RP-proven low-grade disease and similar CAPRA-S scores. RESULTS: With a median follow-up time of 27 months, the overall 7-year FFbF rate was 86% vs. 79% in CS and AA men, respectively (P = 0.035). There was no significant difference in one or more adverse pathologic features between CS vs. AA men (27% vs. 31%; P = 0.35) or CAPRA-S score (P = 0.28). In the subset analysis of patients with low-grade disease, AA race was associated with worse FFbF outcomes (P = 0.002). Furthermore, AA race was a significant predictor of FFbF in men with low-grade disease (hazard ratio = 2.01, 95% CI: 1.08-3.72; P = 0.029). CONCLUSIONS: AA race is a predictor of worse FFbF outcomes in men with low-grade disease after RP. These results suggest that a subset of AA men with low-grade disease may benefit from more aggressive treatment.

Combining targeted agents with modern radiotherapy in soft tissue sarcomas.

Improved understanding of soft-tissue sarcoma (STS) biology has led to better distinction and subtyping of these diseases with the hope of exploiting the molecular characteristics of each subtype to develop appropriately targeted treatment regimens. In the care of patients with extremity STS, adjunctive radiation therapy (RT) is used to facilitate limb and function, preserving surgeries while maintaining five-year local control above 85%. In contrast, for STS originating from nonextremity anatomical sites, the rate of local recurrence is much higher (five-year local control is approximately 50%) and a major cause of death and morbidity in these patients. Incorporating novel technological advancements to administer accurate RT in combination with novel radiosensitizing agents could potentially improve local control and overall survival. RT efficacy in STS can be increased by modulating biological pathways such as angiogenesis, cell cycle regulation, cell survival signaling, and cancer-host immune interactions. Previous experiences, advancements, ongoing research, and current clinical trials combining RT with agents modulating one or more of the above pathways are reviewed. The standard clinical management of patients with STS with pretreatment biopsy, neoadjuvant treatment, and primary surgery provides an opportune disease model for interrogating translational hypotheses. The purpose of this review is to outline a strategic vision for clinical translation of preclinical findings and to identify appropriate targeted agents to combine with radiotherapy in the treatment of STS from different sites and/or different histology subtypes.

Dietary recommendations during and after cancer treatment: consistently inconsistent?

Recent data reveals that dietary factors may influence outcomes in patients undergoing cancer treatment. However, patient-centered information on dietary recommendations is limited. In this study, we assessed dietary recommendations for cancer patients during treatment and survivorship by evaluating the websites of all National Comprehensive Cancer Network (NCCN) member institutions. NCCN members were identified on www.nccn.org , and individual websites were reviewed for nutritional content. Recommendations were categorized by meal frequency, diet type, macronutrient content, and other specific recommendations. Twenty-one NCCN member institutions were identified. Only 4 sites (19%) provided nutritional guidelines. Half promoted a low-fat, high-carbohydrate diet recommending 5:1 and 7:1 ratios of carbohydrate to fat food types, and half promoted weight maintenance during treatment, endorsing a 1:1 ratio of carbohydrate to fat. One third of all NCCN sites (n = 7) had links to 9 external websites. Four external sites provided nutrition guidelines: half favored a low-fat, high-carbohydrate diet, and half favored high-caloric intake to maintain weight. Consistent online dietary recommendations are lacking for patients during and after cancer treatment. Given the lack of consensus on dietary recommendations, future research is warranted to develop evidenced-based guidelines that can be used by oncologists and patients alike.

Nutrient restriction and radiation therapy for cancer treatment: when less is more.

Calorie restriction (CR), or a diet modification aiming to reduce the total intake of calories by 20%-40%, has been shown to increase longevity across multiple species. Recently, there has been growing interest in investigating the potential role of CR as a treatment intervention for age-related diseases, such as cancer, because an increasing body of literature has demonstrated a metabolic component to both carcinogenesis and tumor progression. In fact, many of the molecular pathways that are altered with CR are also known to be altered in cancer. Therefore, manipulation of these pathways using CR can render cancer cells, and most notably breast cancer cells, more susceptible to standard cytotoxic treatment with radiation and chemotherapy. In this review article we demonstrate the laboratory and clinical evidence that exists for CR and show compelling evidence through the molecular pathways CR induces about how it may be used as a treatment in tandem with radiation therapy to improve our rates of disease control.

A phase I study of the combination of sorafenib with temozolomide and radiation therapy for the treatment of primary and recurrent high-grade gliomas.

PURPOSE: Despite recent advances in the management of high-grade and recurrent gliomas, survival remains poor. Antiangiogenic therapy has been shown to be efficacious in the treatment of high-grade gliomas both in preclinical models and in clinical trials. We sought to determine the safety and maximum tolerated dose of sorafenib when combined with both radiation and temozolomide in the primary setting or radiation alone in the recurrent setting. METHODS AND MATERIALS: This was a preclinical study and an open-label phase I dose escalation trial. Multiple glioma cell lines were analyzed for viability after treatment with radiation, temozolomide, or sorafenib or combinations of them. For patients with primary disease, sorafenib was given concurrently with temozolomide (75 mg/m(2)) and 60 Gy radiation, for 30 days after completion of radiation. For patients with recurrent disease, sorafenib was combined with a hypofractionated course of radiation (35 Gy in 10 fractions). RESULTS: Cell viability was significantly reduced with the combination of radiation, temozolomide, and sorafenib or radiation and sorafenib. Eighteen patients (11 in the primary cohort, 7 in the recurrent cohort) were enrolled onto this trial approved by the institutional review board. All patients completed the planned course of radiation therapy. The most common toxicities were hematologic, fatigue, and rash. There were 18 grade 3 or higher toxicities. The median overall survival was 18 months for the entire population. CONCLUSIONS: Sorafenib can be safely combined with radiation and temozolomide in patients with high-grade glioma and with radiation alone in patients with recurrent glioma. The recommended phase II dose of sorafenib is 200 mg twice daily when combined with temozolomide and radiation and 400 mg with radiation alone. To our knowledge, this is the first publication of concurrent sorafenib with radiation monotherapy or combined with radiation and temozolomide.

Patient-oriented cancer information on the internet: a comparison of wikipedia and a professionally maintained database.

PURPOSE: A wiki is a collaborative Web site, such as Wikipedia, that can be freely edited. Because of a wiki's lack of formal editorial control, we hypothesized that the content would be less complete and accurate than that of a professional peer-reviewed Web site. In this study, the coverage, accuracy, and readability of cancer information on Wikipedia were compared with those of the patient-orientated National Cancer Institute's Physician Data Query (PDQ) comprehensive cancer database. METHODS: For each of 10 cancer types, medically trained personnel scored PDQ and Wikipedia articles for accuracy and presentation of controversies by using an appraisal form. Reliability was assessed by using interobserver variability and test-retest reproducibility. Readability was calculated from word and sentence length. RESULTS: Evaluators were able to rapidly assess articles (18 minutes/article), with a test-retest reliability of 0.71 and interobserver variability of 0.53. For both Web sites, inaccuracies were rare, less than 2% of information examined. PDQ was significantly more readable than Wikipedia: Flesch-Kincaid grade level 9.6 versus 14.1. There was no difference in depth of coverage between PDQ and Wikipedia (29.9, 34.2, respectively; maximum possible score 72). Controversial aspects of cancer care were relatively poorly discussed in both resources (2.9 and 6.1 for PDQ and Wikipedia, respectively, NS; maximum possible score 18). A planned subanalysis comparing common and uncommon cancers demonstrated no difference. CONCLUSION: Although the wiki resource had similar accuracy and depth as the professionally edited database, it was significantly less readable. Further research is required to assess how this influences patients' understanding and retention.

Human equilibrative nucleoside transporter 1 levels predict response to gemcitabine in patients with pancreatic cancer.

BACKGROUND & AIMS: The human equilibrative nucleoside transporter (hENT1) protein transports gemcitabine into cells. Small retrospective studies in pancreatic cancer suggest that levels of hENT1 protein or messenger RNA may have prognostic value. We studied the predictive value of hENT1 levels in a cohort of pancreatic adenocarcinoma patients from the large prospective randomized adjuvant treatment trial RTOG9704. METHODS: In RTOG9704, 538 patients were assigned randomly, after surgical resection, to groups that were given either gemcitabine or 5-fluorouracil (5-FU). Immunohistochemistry for hENT1 was performed on a tissue microarray of 229 resected pancreatic tumors from RTOG9704 and scored as having no staining, low staining, or high staining. Associations between hENT1 protein and treatment outcome were analyzed by unconditional logistic regression analysis using the chi-square test and the Cox proportional hazards model. RESULTS: HENT1 expression was associated with overall and disease-free survival in a univariate (hazard ratio [HR], 0.51; 95% confidence interval [CI], 0.29-0.91; P= .02; and HR, 0.57; 95% CI, 0.32-1.00; P= .05) and multivariate model in the group given gemcitabine (HR, 0.40; 95% CI, 0.22-0.75; P= .004; and HR, 0.39; 95% CI, 0.21-0.73; P= .003). hENT1 expression was not associated with survival in the group given 5-FU. CONCLUSIONS: In this prospective randomized trial, hENT1 protein expression was associated with increased overall survival and disease-free survival in pancreatic cancer patients who received gemcitabine, but not in those who received 5-FU. These findings are supported by preclinical data; the gemcitabine transporter hENT1 is therefore a molecular and mechanistically relevant predictive marker of benefit from gemcitabine in patients with resected pancreatic cancer.

In vivo radioprotection by the fullerene nanoparticle DF-1 as assessed in a zebrafish model.

PURPOSE: We have previously shown that zebrafish (Danio rerio) embryos can be used as an in vivo model to validate modifiers of the radiation response. Here, we evaluated the radioprotective effect of the nanoparticle DF-1, a fullerene with antioxidant properties, in zebrafish embryos. EXPERIMENTAL DESIGN: Zebrafish embryos were exposed to different doses of ionizing radiation ranging from 20 to 80 Gy in the presence and absence of DF-1. Toxicity and radioprotective effects were assessed by monitoring overall survival and morphology as well as organ functions by employing assays to measure kidney excretory function and development of sensory nerve cells (neuromasts). Antioxidant properties of DF-1 were assessed in whole fish. RESULTS: DF-1 had no apparent adverse effects on normal zebrafish morphology or viability throughout the concentration range tested (1-1,000 micromol/L). Ionizing radiation (10-40 Gy) caused time-dependent and dose-dependent perturbations of normal zebrafish morphology and physiology, notably defective midline development resulting in dorsal curvature of the body axis ("curly-up"), neurotoxicity, impaired excretory function, and decreased survival of the exposed embryos. DF-1 (100 micromol/L) markedly attenuated overall and organ-specific radiation-induced toxicity when given within 3 hours before or up to 15 minutes after radiation exposure. By contrast, DF-1 afforded no protection when given 30 minutes after ionizing radiation. The degree of radioprotection provided by DF-1 was comparable with that provided by the Food and Drug Administration-approved radioprotector amifostine (4 mmol/L). Protection against radiation-associated toxicity using DF-1 in zebrafish embryos was associated with marked reduction of radiation-induced reactive oxygen species. CONCLUSION: The fullerene DF-1 protects zebrafish embryos against deleterious effects of ionizing radiation due, in part, to its antioxidant properties.

Salvage of suboptimal prostate seed implantation: Reimplantation of underdosed region of prostate base.

PURPOSE: To demonstrate how a suboptimal (125)I prostate implant can be salvaged by reimplantation. METHODS AND MATERIALS: A (125)I implant was preplanned to deliver 150 Gy to the prostate of a patient with early stage prostate cancer. A CT scan at 35 days postimplant indicated that V(100) and D(90) were 46% and 49 Gy, respectively. The cause was a systematic source placement error that left the base significantly underdosed. A reimplantation of the underdosed region was planned by superimposing a template grid onto the 35-day postimplant CT scan images and digitizing them into the treatment planning computer as if they were TRUS images. The reimplantation was carried out under fluoroscopy guidance so that the initial implant was visible. RESULTS: The reimplantation increased V(100) and D(90) to 98% and 201 Gy, respectively. The misplaced seeds resulted in a high dose to the apical region and urethra, which was further increased by the reimplantation. The patient experienced increased urinary morbidity, which was relieved by medication. CONCLUSION: It is feasible to salvage a suboptimal prostate seed implant by reimplanting the underdosed regions under fluoroscopy guidance based on a plan generated from the postimplant CT scan.

Novel use of zebrafish as a vertebrate model to screen radiation protectors and sensitizers.

PURPOSE: Zebrafish (Danio rerio) embryos provide a unique vertebrate model to screen therapeutic agents easily and rapidly because of their relatively close genetic relationship to humans, ready abundance and accessibility, short embryonal development, and optical clarity. To validate zebrafish embryos as a screen for radiation modifiers, we evaluated the effects of ionizing radiation in combination with a known radioprotector (free radical scavenger Amifostine) or radiosensitizing agent (tyrosine kinase inhibitor AG1478). METHODS AND MATERIALS: Viable zebrafish embryos were exposed to 0-10 Gy single-fraction 250 kVp X-rays with or without either Amifostine (0-4 mM) or AG1478 (0-10 microM) at defined developmental stages from 1-24 h postfertilization (hpf). Embryos were examined for morphologic abnormalities and viability until 144 hpf. RESULTS: Radiation alone produced a time- and dose-dependent perturbation of normal embryonic development and survival with maximal sensitivity at doses > or =4 Gy delivered before 4 hpf. Amifostine markedly attenuated this effect, whereas AG1478 enhanced teratogenicity and lethality, particularly at therapeutically relevant (2-6 Gy) radiation doses. CONCLUSIONS: Collectively, these data validate the use of zebrafish as a vertebrate model to assess the effect of radiation alone or with radiation response modulators. Zebrafish embryos may thus provide a rapid, facile system to screen novel agents ultimately intended for human use in the context of therapeutic or accidental radiation exposure.